The present invention relates to the field of organic synthesis and more specifically to a process for the preparation of Michael-adducts, as defined below, by reacting a xcex2,xcex2- or a xcex1,xcex2-disubstituted, or a xcex1,xcex2,xcex2-trisubstituted, xcex1,xcex2-unsaturated ketone (I) with a xcex2-ketoester or a xcex2-diketone (II) in presence of a suitable catalyst of formula M(X)n, according to scheme 1:
To the best of our knowledge, no reaction according to scheme 1 involving a xcex1,xcex2-disubstituted, or a xcex1,xcex2,xcex2-trisubstituted, xcex1,xcex2-unsaturated ketone with a xcex2-ketoester or a xcex2-diketone has been reported in the prior art.
Various processes involving addition reactions between xcex2,xcex2-disubstituted xcex1,xcex2-unsaturated ketones and xcex2-ketoester or a xcex2-diketone in the presence of a base have been reported before. However, they all provide a product which is the result of a so-called Robinson annulation, e.g. as described in J. D. Surmatis et al., J Org. Chem., (1970), 1053.
The coupling of a xcex2,xcex2-disubstituted enone with an alkyl xcex2-ketoester in the presence of 5% of a metal/acac complex (acac being 2,4-pentanedione) and 5% of a Lewis or a Broxc3xansted acid (P. Kocovsky et al., Tetrahedron Lett., (1986), 5015 or P. Kocovsky et al., Coll. Czech. Chem. Commun., (1988), 2667) has also been tried, but the xcex2,xcex2-disubstituted enones used by these authors proved to be inert under a variety of conditions.
Similarly, the direct coupling of the same type of compounds under high pressures (W. G. Dauben et al, Tetrahedron Lett., (1983), 3841), has shown that a Michael-adduct can only be obtained if a highly reactive xcex2,xcex2-disubstituted enone, such as the 3,4,5,6-tetrahydro-1(2H)-pentalenone, is used. Another example of the synthesis of a Michael-adduct, by using highly activated xcex2,xcex2-disubstituted xcex1,xcex2-unsaturated ketones, possessing a Cxe2x95x90C double bond moiety as part of a bycyclic ring, is described in A. M. El-Gendy et al. Asian. J. Chem.; (1990), 2, 168.
U.S. Pat. Nos. 4,939,143 and 4,900,754 report the synthesis of 3,3-dimethyl-2-(4-fluoro-3-methylbenzoyl)-5-oxohexanoate. In said synthesis a xcex2,xcex2-disubstituted enone is reacted with a xcex2-ketoester in presence of a stoechiometric amount of BF3xc2x7OEt2 at 0xc2x0 C. However, this method has the major drawback to need a stoechiometric amount of an expensive, strong and reactive Lewis acid. Furthermore, said method, which has been reported only for the specific reaction described in the US patents, cannot be considered as a general method because if a xcex2-diketone is used instead of xcex2-ketoester then the reaction leads directly to the Robinson annulation product, as described in A. Fernandez-Mateos et al. J. Org. Chem.; (1998), 63, 9440.
Y. L. Chow; Can. J. Chem., (1993), 71, 846 teaches about the photochemical reaction between a xcex2,xcex2-disubstituted enone and a B(acac)F2 complex. Nevertheless, said reaction leads to the formation of several by-products and, additionally, needs a steochiometric amount of BF3.
Although compounds of formula (III) are interesting intermediates in a number of synthesis, and can also be precursors of xcex2,xcex2-disubstituted-xcex4-diketonic or xcex1,xcex2-disubstituted-xcex4-diketonic compounds, to the best of our knowledge, none of the methods reported for their preparation is of general or of simple application.
In order to overcome the difficulties aforementioned, the present invention relates to a simple and general process, aimed at the synthesis of the compounds of formula (III) in a single step.
In this process, the preparation of a compound of formula (III): 
wherein
Q represents a Rxe2x80x2 group, a ORxe2x80x2 group, or a NH2, NHRxe2x80x2 or NRxe2x80x22 group;
R1, Rxe2x80x2 and Rxe2x80x3 represent, independently from each other, an aromatic ring possibly substituted, or a linear or branched C1-C8 alkyl or alkenyl group, possibly substituted;
Rxe2x80x2xe2x80x3 represents a hydrogen atom or a linear or branched C1-C4 alkyl or alkenyl group;
R2, R3, R4, represent, independently from each other, a hydrogen atom or an aromatic ring possibly substituted, or a linear, branched or cyclic C1-C8 alkyl or alkenyl group, possibly substituted, provided that at least two of said R2, R3 and R4 groups do not represent simultaneously an hydrogen atom; or
two of the groups R1 to R4 are bonded together to form a ring having 5 to 15 carbon atoms, said ring being possibly substituted;
characterized in that a xcex2,xcex2- or a xcex1,xcex2-disubstituted, or a xcex1,xcex2,xcex2-trisubstituted, xcex1,xcex2-unsaturated ketone (I) 
wherein R1, R2, R3 and R4 have the same meaning as in formula (III),
is reacted with a xcex2-ketoester or a xcex2-diketone (II) 
wherein Y, Rxe2x80x3 and Rxe2x80x2xe2x80x3 have the same meaning as in formula (III),
in the presence of a catalyst of formula M(X)n, M representing a metal or a group containing a metal, n representing an integer from 1 to 4 and X representing a weakly coordinating or non-coordinating mono-anion.
As non-limiting examples, groups which are possible substituents of R1, R2, R3, R4, Rxe2x80x2, Rxe2x80x3 and of the ring, which two of said Rxe2x80x2 to R4 may form together, are C1-C7 alkyl, alkenyl or alkoxy groups, C5-C7 cycloalkyl or cycloalkenyl groups, or aromatic rings possibly substituted by a C1-C8 alkyl or alkoxy group or a halide atom.
Preferably,
Q represents a Rxe2x80x2 or a ORxe2x80x2 group;
Rxe2x80x2, Rxe2x80x2 and Rxe2x80x3 represent, independently from each other, a linear C1-C5 alkyl or alkenyl group, possibly substituted;
Rxe2x80x2xe2x80x3 represents a hydrogen atom or a linear or branched C1-C3 alkyl group;
R2, R3 and R4 represent a hydrogen atom or a linear C1-C5 alkyl or alkenyl group, possibly substituted, provided that at least two of said R2, R3 and R4 groups do not represent simultaneously an hydrogen atom; or
two of the groups R1 to R4 are bonded together to form a ring having 5 to 8 carbon atoms, said ring being possibly substituted.
As non-limiting examples, groups which are possible substituents of R1, R2, R3, R4, Rxe2x80x2, Rxe2x80x3 and of the ring, which two of said R1 to R4 may form together, are C1-C4 alkyl, alkenyl or alkoxy groups, C5-C6 cycloalkyl or cycloalkenyl groups or aromatic groups possibly substituted by a C1-C6 linear or branched alkyl or alkoxy group or a halide atom.
More preferably, the compound of formula (I) is 4-methyl-3-penten-2-one or 3-methyl-3-penten-2-one, and the compound of formula (JI) is 2,4-pentanedione or a C1-C4 alkyl ester of the 3-oxo-butanoate.
Preferred catalysts of formula M(X)n are those wherein M is selected from the group consisting of the 3d transition metals, the lanthanides, the trimethylsilane group (Me3Si), the vanadyl group (VO3+), the alkaline metals, Sc, Y, Sn, Pb, Al and Bi;
n is an integer from 1 to 3; and
X is selected from the group consisting of CF3SO3xe2x88x92, RSO3xe2x88x92, SbF6xe2x88x92, PF6xe2x88x92, ClO4xe2x88x92, [BF3(RCOCRCOR)]xe2x88x92, [BF3(RCOCRCO2R)]xe2x88x92, [BF3(RCOO)]xe2x88x92, [BF3(RO)]xe2x88x92, BZ4xe2x88x92, Z being a fluoride atom or an alkyl or aryl group possibly substituted, and R representing an C1-C10 aromatic, alkylaromatic or alkyl group, possibly substituted.
Groups which are possible substituents of Z and R are, for example, halides atomts, C1 to C6 alkyl or alkoxy groups or non-coordinatng nitrogen containing groups.
More preferably M is selected from the group consisting of Cu, Zn, Y and Yb;
n is an integer from 1 to 3; and
X is selected from the group consisting of CF3SO3xe2x88x92, C6H5SO3xe2x88x92, CH3C6H4SO3xe2x88x92, CH3SO3xe2x88x92, SbF6xe2x88x92, PF6xe2x88x92, ClO4xe2x88x92, [BF3(acac)]xe2x88x92 (acac representing CH3COCHCOCH3xe2x88x92), [BF3(CH3COO)]xe2x88x92, BF4xe2x88x92 and BPh4xe2x88x92.
In general, the catalyst may be added to the reaction media as a pure and isolated chemical or it can be prepared in situ, by several methods, in the reaction medium, without isolation or purification, just before its use.
One of the possible procedures to advantageously prepare in situ a catalyst according to the invention consists in reacting an appropriate anhydrous metal salt of formula M(acac)n or M(RCOO)n, R being defined as herein above and n being an integer from 2 to 3, with n equivalents, in respect to the metal, of BF3xc2x7OEt2 in a solvent, e.g. an ester. The mixture thus obtained is ready to be used in the process of the invention. Alternatively, it is possible to use a hydrate form of a catalyst of the invention, which is generally commercially available, and to proceed to a dehydration, using any of the conventional methods of the art, prior the use of said catalyst in the process.
The catalyst can be added to the reaction medium in a large range of concentration. As non-limiting examples, one can cite as catalyst concentration values ranging from 0.001 to 0.1 molar equivalents, relative to the xcex1,xcex2-unsaturated ketone (I). Preferably, the catalyst concentration will be comprised between 0.005 and 0.05 molar equivalents. It goes without saying that the optimum concentration of catalyst will depend on the nature of the latter and on the desired time of reaction.
The process of the invention can be carried out in presence or absence of solvent, but in any case it is advantageously performed in anhydrous conditions, wherein by anhydrous is intended a content in water below 1% by weight, preferably below 0.5%. When a solvent is required, it is possible to use a pure solvent or a mixture of solvents. Said solvent is chemically compatible with the reaction and does not deactivate the catalyst, e.g. a weakly or non-coordinating solvent. Preferred solvents for the process of the invention are selected from the group consisting of ethers, carboxylic acids, esters, ketones, aromatic solvent, linear or branched or cyclic hydrocarbons, chlorinated solvents and mixture thereof. More preferably, the solvent is selected from the group consisting of C4-C6 ethers, C2-C8 esters, C3-C6 ketones, acetic acid, methylene chloride and mixture thereof.
The temperature at which the process of the invention can be carried out is comprised between xe2x88x9220xc2x0 C. and 100xc2x0 C., preferably between 0xc2x0 C. and 50xc2x0 C. Of course a person skilled in the art is also able to select the preferred temperature as a function of the melting and boiling point of the starting and final products and/or an eventual solvent.
The process of the invention may also be advantageously carried out under pressure of an inert gas such as nitrogen. In said eventuality, a pressure ranging from 1.5 bar to 20 Kbar, preferably from 2 to 200 bar, may be used.
The invention will now be described in further details by way of the following examples, wherein the abbreviations have the usual meaning in the art, the temperatures are indicated in degrees centigrade (xc2x0 C.); the NMR spectral data were recorded with a 360 MHz machine in CDCl3, the chemical displacement xcex4 are indicated in ppm with respect to the TMS as standard, the coupling constant J are expressed in Hz and all the abbreviations have the usual meaning in the art.